The specific problems in behaviors and cognition that are caused by major neurological diseases including Alzheimer's, Parkinson's, Huntington's, and ALS arise due to the progressive degeneration and dysfunction of neurons in selected regions throughout the brain. Similar causes are also hypothesized for the common decline in behaviors and cognition associated with natural aging. Yet, the entire complement of neurons that become progressively dysmorphic and dysfunctional through natural aging remains unknown. A paradigm shifting approach for discovering drugs that prevent neurodegeneration through natural aging and disease models would be to study the effect of each chemical compound in the entire nervous system of a well-defined model organism in a high-throughput manner. We propose to develop a novel high-throughput screening platform using optics and microfluidics (opto-fluidics) that will enable characterization of each neuron in the whole nervous system within milliseconds with sub-cellular resolution in the genetic model Caenorhabditis elegans. The marriage of an ultra-rapid screening method with novel in vivo models will open the possibility for unbiased screens that do not require any prior knowledge of potential drug targets and pathways. We have chosen C. elegans because it is the only animal with a completely characterized nervous system, is amenable to high-throughput drug screening with microfluidics, and is a validated model for aging and neurological diseases in humans. The proposed opto-fluidics platform will be able to rapidly quantify the morphological integrity of every neuron in an animal's nervous system in milliseconds as they pass through a microfludic channel. Individual neurons can easily be identified by combinatorial expression of diverse fluorescent reporters in a single animal. Besides high-speed quantification capabilities, the ability to automatically interface with 96- or 384-well plates will enable for loading of a large number of populations of worms each treated with a different chemical compound into the opto-fluidics chip. The principles uncovered from these studies will have a profound impact on understanding the neuronal basis for how behavioral performance declines in disease and aging, and how to prevent this decline in humans. PUBLIC HEALTH RELEVANCE: